, et al
Step-up therapy for children with uncontrolled asthma while receiving inhaled corticosteroids
N Engl J Med
; doi:

To determine the best add-on therapy for children with uncontrolled asthma despite the use of conventional low-dose fluticasone (100 μg twice daily), the Childhood Asthma Research and Education Network conducted a randomized triple crossover trial in children 6 to 17 years of age from five US institutions. From 2007 through 2008, children with a physician diagnosis of mild-to-moderate asthma, an ability to perform spirometry, and either a 12% increase in FEV1 response to bronchodilator or a methacholine provocation of 12.5 mg/ml or less causing a 20% fall in FEV1 were enrolled. Participants completed three treatment interventions in random order. Each treatment study period lasted 16 weeks with a four-week washout period between the second and third study periods. The treatments were: fluticasone 250 μg twice daily (inhaled-corticosteroid [ICS] step-up therapy); 100 μg fluticasone plus a long-acting bronchodilator (LABA), salmeterol, 50 μg twice daily (as Advair); or 100 μg fluticasone plus 5 or 10 mg of the leukotriene-receptor antagonist (LTRA) montelukast (Singulair). The primary outcome was the differential response to each of the three step-up therapies for the following asthma control measures: the need for treatment with oral prednisone for acute asthma exacerbations, the number of asthma control days, and FEV1.

Of the 182 enrolled participants, 165 completed at least two of the 16-week crossover periods, and 157 completed all three. Nearly all the children had a differential response to each step-up therapy. In pairwise comparisons, a significantly greater proportion of subjects had a better response to LABA than to either LTRA (relative probability, 1.6; 95% CI, 1.1–2.3; P=.004) or ICS (relative probability, 1.7; 95% CI, 1.2–2.4; P=.002). Better control at baseline predicted a better response to LABA step-up (P=.009).

The authors conclude that there is a ceiling effect of low-dose inhaled corticosteroids in many, though not all, children and that improvement in asthma control requires the addition of a different class of medication. Furthermore, the addition of a LABA was significantly more likely to provide a better response than an increased dose of inhaled corticosteroid or addition of a LTRA.

This report’s conclusion is consistent with previous studies in adults demonstrating that the addition of a LABA is more likely to provide greater clinical benefit than an increased dosage of an inhaled corticosteroid,1 and that the additive effect of a LTRA is modest.2 The FDA warning about the LABAs3 applies primarily to use as single agents without an inhaled corticosteroid. However, data recently reviewed in these pages identified an increased risk of asthma exacerbations among the minority of children with a polymorphism of the β2 adrenergic receptor receiving either a LABA or daily albuterol (see AAP Grand Rounds, May 2010;23:554). Exceptional...

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